Biarylpyrazolyl oxadiazole as potent, selective, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.
Lee
Suk Ho
SH
Central Research Laboratories, Green Cross Corporation, 303 Bojeong-dong, Giheung-gu, Yongin 446-770, Korea.
Seo
Hee Jeong
HJ
Lee
Sung-Han
SH
Jung
Myung Eun
ME
Park
Ji-Hyun
JH
Park
Hyun-Ju
HJ
Yoo
Jakyung
J
Yun
Hoseop
H
Na
Jooran
J
Kang
Suk Youn
SY
Song
Kwang-Seop
KS
Kim
Min-ah
MA
Chang
Chong-Hwan
CH
Kim
Jeongmin
J
Lee
Jinhwa
J
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2